We are searching data for your request:
Upon completion, a link will appear to access the found materials.
As one ages there is a loss of up to 10,000 nerve cells a day. As there are many more nerve cells than are necessary for the proper functioning of the nervous system, it is unlikely that routine loss of nerve cells causes any apparent problems until advanced old age.
Some apparent decreases in functioning include decline in speed of response and ability to integrate what is observed than there is in verbal ability or memory. There is also an age-related decline in intelligence, as measured with standard intelligence tests. Memory is also affected by age.
Blood is a connective tissue. Like all connective tissues, it is made up of cellular elements and an extracellular matrix. The cellular elements—referred to as the formed elements—include red blood cells (RBCs), white blood cells (WBCs), and cell fragments called platelets. The extracellular matrix, called plasma, makes blood unique among connective tissues because it is fluid. This fluid, which is mostly water, perpetually suspends the formed elements and enables them to circulate throughout the body within the cardiovascular system.
Anatomy and physiology of ageing 5: the nervous system
The nervous system controls the activities of all body organs and tissues, receiving input from sensory organs and responding via effector organs. With around 100 billion interconnected neurons, the brain is an extremely complex, and still poorly understood, organ. However we do understand, to some degree, how age affects it, as well as the nervous system as a whole. This fifth article in our series on the anatomy and physiology of ageing describes the age-related changes occurring in the brain, spinal cord and peripheral nerves. These changes lead to a gradual decline in cognitive function and a range of other issues, such as reduced bladder control or postural hypotension, but in health the brain normally continues to function adequately throughout life.
Citation: Knight J, Nigam Y (2017) Anatomy and physiology of ageing 5: the nervous system. Nursing Times [online] 113: 6, 55-58.
Authors: John Knight is senior lecturer in biomedical science Yamni Nigam is associate professor in biomedical science, both at the College of Human Health and Science, Swansea University.
- This article has been double-blind peer reviewed
- Scroll down to read the article or download a print-friendly PDF here to see other articles in this series
The nervous system, along with the endocrine system, controls and integrates the activities of all the body’s organs and tissues. It receives and processes sensory input from organs such as the eyes, ears and skin, and responds through a variety of effector organs.
The main organ of the nervous system is the brain, which, with around 100 billion interconnected neurons, is extremely complex despite decades of research, its function remains poorly understood. Ageing leads to a progressive loss of neurons and depletion of neurotransmitters (Mather, 2016), these changes are usually associated with a gradual decline in cognitive function and influenced by environmental, genetic and lifestyle factors (Nyberg et al, 2012).
Age-related changes to the central nervous system
The ageing brain gradually loses neurons and supporting neuroglial cells (Fig 1). Between the ages of 20 and 60, the brain loses around 0.1% of neurons per year, after which the process speeds up (Esiri, 2007). By the age of 90, brain mass will have decreased by around 11% compared with individuals in their 50s, which equates to a loss of about 150g of neural tissue (Wyss-Coray, 2016). The remaining tissues harbour an increased concentration of potentially harmful materials such as iron, aluminium and free radicals.
Aged neural tissues also show increasing pigmentation, largely due to the deposition of two pigments: one brown, lipofuscin (Ottis et al, 2012), and one black, neuromelanin (Clewett et al, 2016). Lipofuscin is linked to amyloid protein deposition and the formation of neurofibrillary tangles. These abnormal areas of neural tissue are often present at low densities in aged brain tissue, even in the absence of disease (Wyss-Coray, 2016) however, where Alzheimer’s disease is present, these are at high densities.
The loss of neurons is most apparent in the cerebral cortex. The grooves (sulci) that mark the surface convolutions (gyri) of the cerebral cortex are visibly deeper in brains of older people (Fig 1). It was originally thought that the frontal lobes were particularly vulnerable to neural loss, but similar losses have been observed in other cortical regions such as the parietal lobes (Fjell et al, 2014).
Structural changes in the frontal and parietal lobes are related to poor memory. Many people in their 80s have modest levels of amyloid protein deposition and retain their memory, while individuals with higher levels typically have a poorer working (short-term) memory (Nyberg et al, 2012). However, the role of amyloid deposition in impairing memory has recently been questioned and other factors, such as accumulation of tau proteins, may play a more important role (Brier et al, 2016).
The hippocampus has a key role in memory and the acquisition of new skills. With age, it loses a significant amount of neural tissue (Burke and Barns, 2006), which may explain why activities such as learning a new language become more difficult with advancing age. Recent research indicated that navigating a computer-generated virtual environment improved spatial awareness and reduced the shrinkage of the hippocampus, both in younger and older people (Lövdén et al, 2012). Virtual reality computer programs could therefore potentially be used to reduce shrinkage in this vital brain area.
Somatic motor cortex
Around 35% of people over the age of 70 years have gait problems while there are many contributing factors, including age-related changes to muscles and joints, the nervous system is also implicated. The somatic motor cortex – located in the frontal lobes of the brain – controls the movement of muscles involved in walking. From middle age onwards the neurons in this region show signs of atrophy (Manini et al, 2013), which can contribute to gait problems, potentially reducing mobility in older people (Rosso et al, 2013).
Ageing is associated with a gradual increase in the size of the ventricles (fluid-filled chambers) in the brain (Fig 1). This is likely to result from a progressive loss of the cells that line the ventricles. Enlarged ventricles fill with more cerebrospinal fluid, and are readily observable using techniques such as magnetic resonance imaging. On average, the volume of the ventricular system increases by around 2.9% per year this expansion appears to accelerate with age, with people over the age of 70 having a median rate of expansion of 4.25% per year (Raz and Rodrigue, 2006). Although ventricular expansion is seen in most older people, the cognitive impact of this remains unclear.
Brainstem and autonomic function
The medulla oblongata and other areas of the brainstem lose fewer neurons than other regions of the brain. The brainstem is probably the best preserved region of the brain, which probably reflects its essential role in supporting life: it controls breathing, peristalsis, heart rate and blood pressure. However, the autonomic function of the brain does decline with age and this can compromise the body’s ability to respond quickly to internal and external environmental changes (Hotta and Uchida, 2010). Both branches of the autonomic nervous system (ANS) – the parasympathetic and sympathetic branches – are compromised with age (Parashar et al, 2016).
These changes can negatively affect older people. For example, the blunting of baroreceptor responses increases the risk of postural hypotension, so standing up suddenly can lead to falls and injury. Another negative consequence is the gradual loss of bladder control. To control micturition, the body relies on the interplay of sensory stretch receptors and the ANS (which together monitor bladder filling) and the conscious areas of the cerebral cortex (which signals when the bladder is full). To initiate micturition, the body needs motor control of the urinary sphincter. All these elements function less well with age, and these age-related changes combine with those in other body systems – such as prostate enlargement in men and weakened pelvic floor muscles in women – to reduce bladder sensitivity and control (Hotta and Uchida, 2010), which can lead to continence problems.
Cerebral blood flow and the blood-brain barrier
Cerebral blood flow decreases by around 0.38% per year, equating to a 27% decline over 70 years of life (Chen et al, 2011). This is a direct consequence of the age-related changes in the cardiovascular system, and may be exacerbated in patients with atherosclerotic occlusion of the carotid arteries.
The blood-brain barrier (BBB) is formed primarily of tight junctions between adjacent endothelial cells within the blood vessels in the brain. Additionally, specialised neuroglial cells called astrocytes wrap around the cerebral vessels, forming a further physical barrier between the blood and neural tissues. The BBB is essential to prevent most pathogens and many toxic materials crossing into the neural networks and pathways of the brain, but its integrity appears to diminish with age. A recent study indicates that, during normal ageing, the BBB is first weakened in the hippocampus, thereby allowing harmful substances and pro-inflammatory mediators to cross into this vital region of learning and memory. This breaching of the BBB may contribute to hippocampal shrinkage, and therefore to cognitive decline (Montagne et al, 2015).
Ageing is associated with a declining production of many neurotransmitters, including noradrenaline, glutamate, dopamine and serotonin. The decline in dopamine appears to be particularly important: dopamine modulates motor function and the acquisition of new skills, while also acting as one of the brain’s reward chemicals (Mather, 2016). The number of dopamine-producing neurons decreases as part of the normal ageing process, and this can adversely affect the ability to learn from past experiences. Recent studies show that many older people who boosted their levels of dopamine by taking L-DOPA (a drug normally used to treat Parkinson’s disease) were learning as quickly as young adults again (Chowdhury et al, 2013).
Few studies have examined age-related changes to the spinal cord. A recent animal-model study shows an increase of cholesterol content in the ageing spinal cord, and the authors suggest this may potentially impair cord function (Parkinson et al, 2016).
Age-related changes to neurons and neuroglial cells appear to have little effect on spinal cord function. However, age-related changes to the vertebrae and intervertebral discs may increase pressure on the spinal cord and its branching nerve roots. This can slow down the conduction of nerve impulses along motor neurons, contributing to reduced muscular strength (Manini et al, 2013). Reduced sensory and motor conduction will increase the risk of injury due to poor coordination, poor balance and poor fine motor control.
Age-related changes to the peripheral nervous system
With age, some peripheral neurons show a ‘dying back’ (shrinkage of axonal length), loss of mitochondria and a degeneration of their insulatory myelin sheaths. Some of this damage may be caused by a rise in the concentrations of pro-inflammatory mediators in the body. The ageing body becomes less effective in clearing toxic metabolites and, as peripheral nerves are not afforded the protection of the BBB, this may contribute to peripheral nerve damage (Manini et al, 2013).
The loss of myelin slows the conduction of peripheral nerve impulses by around 5-10% (Joynt, 2000). In health, this reduction in conductivity causes few problems, but in older people with diabetes it may contribute to, and exacerbate, diabetic neuropathy. Damaged peripheral nerves are not repaired as efficiently in older people as in their younger counterparts, and some of these nerves are never repaired. This can contribute to reduced sensation and motor control.
How does age affect brain function?
In the absence of disease, intellectual ability can be retained throughout life. However, the gradual loss of neurons, depletion of neurotransmitters and slowing of nerve conduction may act together to slow down the processing of information. As a result, older people may take longer to complete certain tasks, and commonly experience the functional brain changes described below.
Short-term and episodic memory
The loss of short-term and episodic memory is probably the earliest indication of age-related changes in the brain. Unlike what happens in dementia, the loss of short-term memory in the absence of disease does not affect life skills (such as the ability to cook), but manifests as inconveniences (such as forgetting an item from the shopping list). Episodic memory (that is, remembering autobiographical events and their timings and sequence) also gradually declines in many older people (Fjell et al, 2014).
Verbal and word skills
Verbal communication skills generally remain strong throughout life (Park and Reuter-Lorenz, 2009), but people over the age of 70 years may have increasing problems using or recalling words. The ability to quickly name a common object usually remains stable up to the age of 70, but then declines with advancing years (Harada et al, 2013).
The progressive loss of neurons, reduction in impulse velocity and minor changes in the spinal cord lead to a slowing down of reaction times (Spirduso, 1995). This can create problems, particularly when a fast reaction is essential (for example, to step out of the way of oncoming traffic).
In England, around 22% of men and 28% of women over the age of 65 are affected by depression in care homes, the figures are even greater, with around 40% of residents affected (Age UK, 2017).
It is almost impossible to determine whether depression in older people occurs as a normal consequence of ageing or as a result of chemical imbalances seen in types of depression that also affect younger people. Concentrations of neurotransmitters involved in lifting mood (particularly serotonin) diminish with age and this can contribute to symptoms of depression (Fidalgo et al, 2013). The Royal College of Psychiatrists estimates that >85% of depressed older people receive no help from the NHS (Age UK, 2017). Depression can often produce symptoms that mimic dementia (pseudo-dementia) and this often causes great anxiety.
On the whole, older people are less prone to emotional outbursts than younger people. This may be related to the relative structural stability of some of the brain regions linked to emotions. Most studies of the amygdalae – which are heavily involved in impulsive behaviours and emotional reactions – reveal little evidence of atrophy or shrinkage at a much slower rate than in other brain regions. Additionally, the amygdalae also appear to retain most of their functional activity in older age (Mather, 2016).
Because the overall neural mass reduces with age, neuroactive drugs such as antidepressants and neuroleptics can be more potent in older people. Doses normally prescribed to adults may induce confusion or delirium, and may therefore need to be adjusted.
Normal versus pathological changes to the brain
How normal age-related changes to the brain can be distinguished from pathological changes associated with dementia (for example, Alzheimer’s disease) is hotly debated. The problem is that three of the main clinical features of Alzheimer’s disease – loss of episodic memory, loss of brain tissue and amyloid deposition – are also seen in apparently healthy older people with little or no evidence of dementia. However, it is generally recognised that the main risk factor for developing dementia is advancing age (Fjell et al, 2014).
Brain reserve and cognitive reserve
Unlike cells in many other parts of the human body, most neurons do not undergo cell division so, when they die as a result of age or injury, they are generally not replaced. Fortunately, the brain contains over 100 billion interconnected neurons (the connectome) and many researchers agree that it has an in-built redundancy, known as the brain reserve. This is defined as the physical resources of the brain in terms of brain mass and number of neurons a larger brain reserve is often associated with better outcomes after brain injury and in various neurological diseases (Tucker and Stern, 2011).
The brain reserve is not necessarily a good predictor of cognitive function (many people with normal cognition have significant brain atrophy), so the concept of cognitive reserve has emerged. People with a high cognitive reserve are able to use their brain reserve more efficiently to perform tasks, and this seems to happen through increased efficiency of functional connections between neurons (Marques et al, 2016).
Good predictors of a high cognitive reserve include high education level, high IQ, highly complex occupation and large amount of social interaction. Recent research indicates that cognitive ability may also be maintained by neural compensation, a process in which new circuits of neurons are recruited to perform tasks that were once carried out by aged or damaged neural pathways (Steffener and Stern, 2012). In normal ageing, the brain reserve does decline but cognition is maintained thanks to the brain’s in-built redundancy.
Encouraging healthy mental ageing
Keeping mentally active throughout life can reduce the effects of age on the nervous system (Mahncke et al, 2006), and engaging in social, sporting and mentally challenging activities can slow down the decline in cognitive performance (Nyberg et al, 2012). It appears the more intellectually demanding and complex an individual’s occupation, the better their cognitive performance in later years however, in retirement, when the mental challenges of work are removed, this effect appears to decline.
Older people should be encouraged to engage in stimulating activities such as socialising, reading and games, which are thought to improve cognitive function and memory, as well as reduce the risk of depression. It is a common misconception that ageing naturally leads to conditions such as confusion, dementia and delirium. The human brain’s in-built redundancy allows it to adequately cope with the physical changes associated with ageing. Indeed, in the absence of disease, adequate mental function can be retained throughout life.
- As the brain ages, neurons reduce in number, neuro-transmitters are depleted, blood flow reduces and the blood-brain barrier weakens
- Age-related problems of the nervous system include gait issues, postural hypotension, reduced bladder control and loss of short-term memory
- It is often difficult to distinguish normal age-related changes to the brain from pathological changes associated with dementia
- In normal ageing, the brain reserve declines but cognition is maintained thanks to its in-built redundancy and neural compensation
- Keeping mentally active throughout life can reduce the effects of age on the nervous system
Also in this series
Age UK (2017) Later Life in the United Kingdom, January 2017. London: Age UK.
Brier MR et al (2016) Tau and Aß imaging, CSF measures, and cognition in Alzheimer’s disease. Science Translational Medicine 8: 338, 338ra66.
Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nature Reviews Neuroscience 7: 1, 30-40.
Chen JJ et al (2011) Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage 55: 2, 468-478.
Chowdhury R et al (2013) Dopamine restores reward prediction errors in old age. Nature Neuroscience 16: 5, 648-653.
Clewett DV et al (2016) Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiology of Aging 37: 117-126.
Esiri MM (2007) Ageing and the brain. Journal of Pathology 211: 2, 181-187.
Fidalgo S et al (2013) Serotonin: from top to bottom. Biogerontology 14: 1, 21-45.
Fjell AM et al (2014) What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Progress in Neurobiology 117: 20-40.
Harada CN et al (2013) Normal cognitive aging Clinics in Geriatric Medicine 29: 4, 737-752.
Hotta H, Uchida S (2010) Aging of the autonomic nervous system and possible improvements in autonomic activity using somatic afferent stimulation. Geriatrics and Gerontology International 10: Suppl 1, S127-S136.
Joynt RJ (2000) Aging and the nervous system. In: The Merck Manual of Geriatrics. West Point PA: Merck & Co.
Lövdén M et al (2012) Spatial navigation training protects the hippocampus against age-related changes during early and late adulthood. Neurobiology of Aging 33: 3, 620.e9-620.e22.
Mahncke HW et al (2006) Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study. Proceedings of the National Academy of Sciences of the United States of America 103: 33, 12523-12528.
Manini TM et al (2013) Aging and muscle: a neuron’s perspective. Current Opinion in Clinical Nutrition and Metabolic Care 16: 1, 21-26.
Marques P et al (2016) The functional connectome of cognitive reserve. Human Brain Mapping 37: 9, 3310-3322.
Mather M (2016) The affective neuroscience of aging. Annual Review of Psychology 67: 213-238.
Montagne A et al (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85: 2, 296-302.
Nyberg L et al (2012) Memory aging and brain maintenance. Trends in Cognitive Sciences 16: 5, 292-305.
Ottis P et al (2012) Human and rat brainlipofuscin proteome. Proteomics 12: 15-16, 2445-2454.
Parashar R et al (2016) Age related changes in autonomic functions. Journal of Clinical and Diagnostic Research 10: 3, CC11-CC15.
Park DC, Reuter-Lorenz P (2009) The adaptive brain: aging and neurocognitive scaffolding. Annual Review of Psychology 60: 173-196.
Parkinson GM et al (2016) Perturbed cholesterol homeostasis in aging spinal cord. Neurobiology of Aging 45: 123-135.
Raz N, Rodrigue KM (2006) Differential aging of the brain: patterns, cognitive correlates and modifiers. Neuroscience and Biobehavioral Reviews 30: 6, 730-748.
Rosso AL et al (2013) Aging, the central nervous system, and mobility. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 68: 11, 1379-1386.
Spirduso WW (1995) Physical Dimensions of Aging. Champaign, Il: Human Kinetics.
Steffener J, Stern Y (2012) Exploring the neural basis of cognitive reserve in aging. Biochimica et Biophysica Acta 1822: 3, 467-473.
Tucker AM, Stern Y (2011) Cognitive reserve in aging. Current Alzheimer Research 8: 4, 354-360.
Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539: 7628, 180-186.
BZDs act as positive allosteric modulators on the gamma amino butyric acid (GABA)-A receptor. The GABA-A receptor is a ligand-gated chloride-selective ion channel.
GABA is the most common neurotransmitter in the central nervous system, found in high concentrations in the cortex and limbic system. GABA is inhibitory in nature and thus reduces the excitability of neurons. GABA produces a calming effect on the brain. 2 The 3 GABA receptors are designated A, B, and C. This article focuses primarily on the GABA-A receptor, with which BZDs interact.
The GABA-A receptor complex is composed of 5 glycoprotein subunits, each with multiple isoforms ( Figure 1 ). GABA-A receptors contain 2 α subunits, 2 β subunits, and 1 γ subunit. Each receptor complex has 2 GABA-binding sites but only 1 BZD-binding site. The benzodiazepine binding site is in a specific pocket at the pairing (intersection) of the α and γ subunits. Within the α subunit of isoforms 1, 2, 3, and 5 resides a histidine residue (H101, H101, H126, and H105, respectively) that possesses a high affinity for BZDs. 3 Isoforms 4 and 6 of the α subunit contain an arginine residue and do not have an affinity for BZDs. 3 BZDs bind to the pocket created by the α and γ subunits and induce a conformational change in the GABA-A receptor, allowing GABA to bind. BZDs bind to the pocket created by α and γ subunits and induce a conformational change in the GABA-A receptor. This alteration, in turn, induces a conformational change in the GABA-A receptor's chloride channel that hyperpolarizes the cell and accounts for GABA's inhibitory effect throughout the central nervous system. 3
Gamma amino butyric acid receptor with target sites. Adapted from http://ccforum.com/content/12/S3/S4/figure/F1.
Specific Benzodiazepine Receptors
The BZD receptor has been classified into several types, based on α subunit isoforms and clinical effects related to each type. The BZ1 receptor contains the 㬑 isoform. The BZ1 receptor is highly concentrated in the cortex, thalamus, and cerebellum 4,5 it is responsible for the BZDs' sedative effects 6 and anterograde amnesia and for some of the anticonvulsive effects of diazepam. 7 Sixty percent of GABA-A receptors contain the 㬑 subunit. Therefore, amnesia is a common side effect of BZD use because the majority of GABA-A receptors contain the BZ1 receptor responsible for amnesia. 8 A major factor in predicting amnesia risk is lipid solubility the greater the lipid solubility, the greater the risk of amnesia. BZDs with high lipid solubility have higher absorption rates and faster onset of clinical effects than BZDs with low lipid solubility. 2
BZ2 receptors contain the 㬒 isoform 4 and mediate the anxiolytic and, to a large extent, the myorelaxant effects of BZDs. 6 BZ2 receptors are highly concentrated in areas such as the limbic system, motor neurons, and the dorsal horn of the spinal cord. 7 The anxiolytic effects of BZDs are believed to be mediated through BZ2 receptors located in the limbic system, and myorelaxant properties are mediated via 㬒-containing receptors in the spinal cord and motor neurons. 7 Not all BZDs interact with the same type of BZ receptor or with equal affinity to a specific receptor. These differences in α subunit isoforms, BZ receptor type affinity, and location within the central nervous system account for the different effects of the various BZDs. 7
The pharmacokinetic properties of a drug determine its onset of action and the duration of its effect. Specifically, pharmacokinetics describes the absorption, distribution, metabolism, and excretion of a drug (ie, what the body does to the drug). Pharmacodynamics describes the responsiveness of receptors to a drug and the mechanism by which these effects occur (ie, what the drug does to the body). Individuals respond differently to the same drug, and often these different responses reflect the pharmacokinetics and/or pharmacodynamics among different patients.
Pharmacokinetics (determination of the onset of action and the duration of drug effect) is affected by route of administration, absorption, and volume of distribution. BZDs can be administered via intramuscular, intravenous, oral, sublingual, intranasal, or rectal gel forms. Characteristics of the drug—including lipid solubility, binding to plasma proteins, and molecular size—influence the volume of distribution. Pharmacodynamics and pharmacologic drug effects are described in terms of dose-response curves that depict the relationship between the dose and the resulting pharmacologic effect. Dose-response curves predict the effect of the drug on the patient as doses increase. Titration of a drug should proceed based on the expected pharmacodynamics. Key considerations during titration of medications include making the appropriate choice for the patient's condition (eg, renal failure, liver failure, previous drug exposure), appropriate choice of incremental dosing (ie, time and quantity), and periodic monitoring. 9
Preexisting disease processes and age-related changes affect elimination half-life, an especially important consideration when administering BZDs. Elimination half-life is the time necessary for plasma concentration of a drug to decrease to 50% during the elimination phase. Because elimination half-life is directly proportional to the volume of distribution and inversely proportional to its clearance, renal and hepatic disease (altered volume of distribution and/or clearance) affect elimination half-life.
Elimination half-life does not reflect time to recovery from drug effects. Elimination half-life is an estimate of the time needed to reduce the drug concentration in the plasma by half. After about 5 elimination half-lives, a drug is nearly totally eliminated from the body. Therefore, drug accumulation is likely if dosing intervals are less than this period of time.
From a pharmacological perspective, BZDs are usually well absorbed by the gastrointestinal tract after oral administration. After intravenous administration, BZDs quickly distribute to the brain and central nervous system. BZD activity is terminated by redistribution similar to that of the lipid-soluble barbiturates. Following intramuscular injection, absorption of diazepam or chlordiazepoxide is slow and erratic, whereas absorption of intramuscular administration of lorazepam or midazolam appears to be rapid and complete. Lorazepam is well absorbed after sublingual administration, reaching peak levels in 60 minutes. 2
BZDs and their metabolites are highly protein bound. They are widely distributed in the body and preferentially accumulate in lipid-rich areas such as the central nervous system and adipose tissue. As previously mentioned, the more lipophilic agents generally have the highest rates of absorption and fastest onset of clinical effects. Most BZDs are oxidatively metabolized by the cytochrome P450 enzymes (phase I), conjugated with glucuronide (phase II), and excreted almost entirely in the urine.
Some BZDs exert additional action via production of active metabolites, an important consideration when prescribing these agents. Midazolam, one of the short-acting BZDs, produces no active metabolites. However, diazepam, a long-acting BZD, produces the active metabolites oxazepam, desmethyldiazepam, and temazepam these metabolites further increase the duration of drug action and should be a serious consideration in some patient groups, especially the elderly and those with extensive hepatic disease. 2
La réponse classique de lutte ou de fuite à une menace perçue est un phénomène nerveux rຟlexe dont les avantages pour la survie sont évidents en termes d'évolution. Cependant, les systèmes organisés en constellation de comportements rຟlexes de survie après exposition à une menace perçue peuvent se déréguler dans certaines circonstances. Une dysregulation chronique de ces systèmes peut entraîner un dຟicit fonctionnel chez certains sujets qui deviennent « psychologiquement traumatisés » ef souffrent de l'état de stress posi-traumatique (ESPT), Des donnພs recueillies pendant des dizaines d'annພs montrent des anomalies neurobiologiques chez les patients souffrant d'ESPT, ce qui permet de mieux comprendre la physiopathologie de l'ESPT ainsi que la vulnérabilité biologique de certaines populations à développer un ESPT, Certaines caractéristiques pathologiques de l'ESPT se superposent à celles trouvພs chez des patients atteints de lésion cérປrale traumatique, en parallèle avec les signes et les symptômes partagés par ces deux syndromes.
The outermost multinucleated syncytial cell layer of the trophoblast, which covers the chorionic villi. It is formed by fusion of the underlying layer of mononuclear trophoblast cells, and forms a barrier between the fetus and the mother.
The process of transport of material across a cell layer by uptake on one side of the cell into a coated vesicle. The vesicle might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.
The surface layer of the normal small intestine that is comprised of small microvilli coated in a rich glycocalyx of mucus and other glycoproteins. The microvilli contain many of the digestive enzymes and transporter systems that are involved in the surface digestion and uptake of dietary materials. It provides a large surface area for absorption.
The prototypic structure of MHC class I molecules and the related MHC class Ib molecules. The heavy chain polypeptide forms an α-helical sandwich that sits on top of an immunoglobulin domain. The heavy chain polypeptide pairs non-covalently with β2-microglobulin.
Immune-privileged sites are areas in the body with a decreased immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and placenta.
A barrier formed by tight junctions between endothelial cells that markedly limits entry to the central nervous system by leukocytes and all large molecules, including to some extent immunoglobulins, cytokines and complement proteins.
Sites of amyloid-β accumulation and dystrophic neurites in the brains of mouse models and patients with Alzheimer's disease.
A sequence of amino acids, which is often rich in cysteine and proline residues, that is present in the constant region of immunoglobulin heavy chains. It provides increased molecular flexibility. This region might be involved in the disulphide bonds that link adjacent immunoglobulin heavy chains.
Staphylococcal protein A and streptococcal protein G
Proteins expressed on the cell surface of Staphylococcal or Streptococcal species. These proteins bind to the heavy chain of IgG antibodies from various species and therefore can be used in antibody isolation and purification.
An antibody (usually IgM) that binds to the Fc region of IgG thereby forming immune complexes. Rheumatoid factors are sometimes found in patients with rheumatoid arthritis and other autoimmune diseases such as systemic lupus erythematosus.
Mice lacking certain genes of interest but transgenically expressing the human equivalent. Such mice provide an easy model system to study the biology of human genes.
Neuroscience For Kids
To investigate the changes that the brain undergoes during aging, neuroscientists use brain imaging methods to observe the anatomy and physiology of the living brain. Scientists can also study autopsy specimens to investigate how the brain changes over time.
- Enlargement of the ventricular system: as people get older, the volume of the ventricles (the spaces in the brain that contain cerebrospinal fluid) increases. It is thought that this enlargement occurs because cells surrounding the ventricles are lost.
- Widening of sulci (the grooves) on the surface of the brain.
- Reduced brain weight and brain volume: these changes are probably caused by the loss of neurons. Reductions in the size of many areas of the cerebral cortex have been reported.
- Neurological disorders: brain disorders such as Alzheimer's disease, Parkinson's disease and stroke are more common in the elderly.
Changes in the Senses
- Lens: proteins in the lens change with age and the elasticity of the lens is reduced. Therefore, many elderly individuals have trouble focusing their eyes. Exposure to ultraviolet light can also yellow the lens. Changes in the lens may affect color vision.
- Cornea: the cornea may become less transparent and more flat. This may cause images to appear distorted or blurred. There may also be a loss of color sensitivity to green, blue and violet shades.
- Pupil: changes in the autonomic nervous system alter the ability of older people to dilate the pupil. By age 70, the pupil may not dilate easily in low lighting conditions (Hampton, 1997).
- Cataracts: cloudy areas of the lens. Cataracts decrease the amount of light that passes through the lens and can bend light abnormally. The National Eye Institute estimates that more than 50% of Americans age 65 years and olderhave a cataract.
- Retina: the peripheral retina is thinner and contains fewer rods in older individuals.
- Other disorders of the eye common in the elderly: glaucoma, macular degeneration, presbyopia.
- Changes in the nasal mucosa, cribriform plate and air passages may contribute to impaired odor recognition.
- The amygdala and other brain areas involved with smell may be damaged in older individuals.
Impairment in the ability to taste may be caused by:
- Medications that the elderly need.
- Reductions in the number of taste buds.
- Dentures that cover taste buds on the soft palate.
Hearing loss in the elderly may result from:
- Ear wax build up.
- Stiffening of the tympanic membrane (eardrum).
- Atrophy of small ear muscles.
- Degeneration of hair cells and support cells in the cochlea.
- Stiffening of basilar membrane.
- Loss of nerve fibers leading from the cochlea to the brain.
- Loss of neurons in auditory areas of the brain.
Age-related changes in the ability to perceive tactile stimuli may be due to:
“Hot Spots” of Aging and Disease Revealed by How Brain Cells Repair Their DNA
Neurons lack the ability to replicate their DNA, so they’re constantly working to repair damage to their genome. Now, a new study by Salk scientists finds that these repairs are not random, but instead focus on protecting certain genetic “hot spots” that appear to play a critical role in neural identity and function.
The findings, published in the April 2, 2021, issue of Science, give novel insights into the genetic structures involved in aging and neurodegeneration, and could point to the development of potential new therapies for diseases such Alzheimer’s, Parkinson’s and other age-related dementia disorders.
In this image of a neuron nucleus, bright spots show areas of focused genetic repair. Credit: Salk Institute/Waitt Advanced Biophotonics Center
“This research shows for the first time that there are sections of genome that neurons prioritize when it comes to repair,” says Professor and Salk President Rusty Gage, the paper’s co-corresponding author. “We’re excited about the potential of these findings to change the way we view many age-related diseases of the nervous system and potentially explore DNA repair as a therapeutic approach.”
Unlike other cells, neurons generally don’t replace themselves over time, making them among the longest-living cells in the human body. Their longevity makes it even more important that they repair lesions in their DNA as they age, in order to maintain their function over the decades of a human life span. As they get older, neurons’ ability to make these genetic repairs declines, which could explain why people develop age-related neurodegenerative diseases like Alzheimer’s and Parkinson’s.
To investigate how neurons maintain genome health, the study authors developed a new technique they term Repair-seq. The team produced neurons from stem cells and fed them synthetic nucleosides—molecules that serve as building blocks for DNA. These artificial nucleosides could be found via DNA sequencing and imaged, showing where the neurons used them to make repairs to DNA that was damaged by normal cellular processes. While the scientists expected to see some prioritization, they were surprised by just how focused the neurons were on protecting certain sections of the genome.
“What we saw was incredibly sharp, well-defined regions of repair very focused areas that were substantially higher than background levels,” says co-first and co-corresponding author Dylan Reid, a former Salk postdoctoral scholar and now a fellow at Vertex Pharmaceutics. “The proteins that sit on these ‘hot spots’ are implicated in neurodegenerative disease, and the sites are also linked to aging.”
The authors found approximately 65,000 hot spots that covered around 2 percent of the neuronal genome. They then used proteomics approaches to detect what proteins were found at these hot spots, implicating many splicing-related proteins. (These are involved in the eventual production of other proteins.) Many of these sites appeared to be quite stable when the cells were treated with DNA-damaging agents, and the most stable DNA repair hot spots were found to be strongly associated with sites where chemical tags attach (“methylation”) that are best at predicting neuronal age.
From left: Rusty Gage and Dylan Reid. Credit: Salk Institute, Dylan Reid
Previous research has focused on identifying the sections of DNA that suffer genetic damage, but this is the first time researchers have looked for where the genome is being heavily repaired.
“We flipped the paradigm from looking for damage to looking for repair, and that’s why we were able to find these hot spots,” Reid says. “This is really new biology that might eventually change how we understand neurons in the nervous system, and the more we understand that, the more we can look to develop therapies addressing age-related diseases.”
Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, adds, “Understanding which areas within the genome are vulnerable to damage is a very exciting topic for our lab. We think Repair-seq will be a powerful tool for research, and we continue to explore additional new methods to study genome integrity, particularly in relation to aging and disease.”
Reference: “Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons” by Dylan A. Reid, Patrick J. Reed, Johannes C. M. Schlachetzki, Ioana I. Nitulescu, Grace Chou, Enoch C. Tsui, Jeffrey R. Jones, Sahaana Chandran, Ake T. Lu, Claire A. McClain, Jean H. Ooi, Tzu-Wen Wang, Addison J. Lana, Sara B. Linker, Anthony S. Ricciardulli, Shong Lau, Simon T. Schafer, Steve Horvath, Jesse R. Dixon, Nasun Hah, Christopher K. Glass and Fred H. Gage, 2 April 2021, Science.
Other authors on the study are Patrick Reed, Ioana Nitulescu, Enoch Tsui, Jeffrey Jones, Claire McClain, Simon Schafer, Grace Chou, Tzu-Wen Wang, Nasun Hah, Sahaana Chandran and Jesse Dixon of Salk Johannes Schlachetzki, Addison Lana, and Christopher Glass of the University of California, San Diego Ake Lu and Steve Horvath of the University of California, Los Angeles.
The research was supported by the American Heart Association, the Paul G. Allen Frontiers Group, the JPB Foundation, the Dolby Foundation, the Helmsley Charitable Trust, and the National Institutes of Health.
New mechanism for sensing and regulating pH in the nervous system
The spinal cord has its own system for sensing changes in pH, according to a study by researchers at Karolinska Institutet. The new findings, which are published in Current Biology, show that cells in the central canal of the spinal cord detect and regulate pH, if it deviates from normal levels. Such changes may in turn impair the function of the neural networks of the nervous system.
The spinal cord conveys nerve signals between the different organs of the body and the brain, and it controls all our movements. Running in the midline through the cord is a thin tube called the central canal, which extends from the brain all the way down to the caudal vertebrae. The canal contains the cerebrospinal fluid (CSF), which flows around the brain and the spinal cord, and is coated with ciliated cells. The function of these cells has long eluded researchers and has been the object of much speculation.
"We have now shown that they operate as sensors that detect the acidity – the pH, that is – of the CSF," says Sten Grillner at Karolinska Institutet's Department of Neuroscience. "These pH sensors in the central canal demonstrate an
elegant mechanism of detecting fluctuations in pH."
Two types of molecules
Each cell has two types of molecules in its cell membrane that detect pH levels, one reacting to acidic pH (called ASIC3) and the other to alkaline pH levels (called PKD2L1). The normal pH of the body is 7.4. These ciliated neurons are highly sensitive to even small deviations from the norm and disruption of the acid-base balance. The researchers behind the current study show that at a pH of 7.4, the cells have a very low level of activity, but as soon as the pH deviates from this value, in either the acidic or the alkaline direction, the activity level increases markedly through the activation of either the ASIC3 molecules (acidic) or the PKD2L1 molecules (alkaline).
Deviations in pH lead to changes in the highly regulated micro-circuits of the nervous system, and an impairment of their normal function. It is therefore vital that it can sense pH levels.
When the nerve system is active, it releases lactic acid metabolically, and at high levels of activity, such as during intense exercise or epilepsy, this causes the pH in the nerve system to become more acidic. Under certain circumstances that affect the metabolism, there can instead be an increase in pH in the alkaline direction. The researchers show that both a lower (more acidic) pH and a higher pH (alkaline) has an inhibitory effect on the motor activity in the spinal cord. This occurs through the secretion of a neurotransmitter called somatostatin from nerve terminals of the pH-sensing central canal cells distributed within the spinal cord itself.
"When the central canal cells detect a change in pH, it thus gives rise to inhibition of the spinal cord's motor circuits, which results in a depression of the motor activity," says Professor Grillner. "This, in turn, helps the pH levels to return to normal."
The study was financed with grants from the Swedish Research Council, the EU's Seventh Framework Programme, Karolinska Institutet's research funds, the Centre National de la Recherche Scientifique and the Muséum National d´Historie Naturelle.
Feature: Human Biology in the News
The most common cause of blindness in the Western hemisphere is age-related macular degeneration (AMD). Approximately 1.4 million people in Canada have this type of blindness, and 196 million people are affected worldwide and is expected to increase to 288 millions people by the year 2040. At present, there is no cure for AMD. The disease occurs with the death of a layer of cells called retinal pigment epithelium, which normally provides nutrients and other support to the macula of the eye. The macula is an oval-shaped pigmented area near the center of the retina that is specialized for high visual acuity and has the retina’s greatest concentration of cones. When the epithelial cells die and the macula is no longer supported or nourished, the macula also starts to die. Patients experience a black spot in the center of their vision, and as the disease progresses, the black spot grows outward. Patients eventually lose the ability to read and even to recognize familiar faces before developing total blindness.
In 2016, a landmark surgery was performed as a trial on a patient with severe AMD. In the first ever operation of its kind, Dr. Pete Coffey of the University of London implanted a tiny patch of cells behind the retina in each of the patient’s eyes. The cells were retinal pigmented epithelial cells that had been grown in a lab from stem cells , which are undifferentiated cells that can develop into other cell types. Within six months of the operation, the new cells were still surviving, and the doctor was hopeful that the patient’s vision loss would stop and even be reversed. At that point, several other operations had already been planned to test the new procedure. If these cases are a success, Dr. Coffey predicts that the surgery will become as routine as cataract surgery, and that it will prevent millions of patients from losing their vision.